Changes in brain metabolism which occur during ischemia and recirculation have continued to be investigated in the gerbil bilateral ischemia model. While previous studies have focused on regional differences in metabolism related to the selective vulnerability of hippocampal CA 1 neurons, major emphasis in current work has been on the temporal relationships between metabolic events and their experimental manipulation. Microwave fixation has allowed the detailed analysis of metabolic changes which occur during the first minute of ischemia, with the demonstration that pentobarbital pretreatment does not prevent, but rather delays the rapid fall in high energy phosphate equivalents during ischemia. Alterations in levels of brain [K+]e and [Ca++]e have been correlated with metabolite changes during ischemia and recirculation in anesthetized gerbils. Anoxic depolarization occurs at approximately 1.5 min ischemia, with a rapid increase in [K+]e and a decrease in [Ca++]e which gradually recover during recirculation. While glucose and phosphocreatine levels are depleted by the time of anoxic depolarization, ATP levels have not fallen below 50% of control. Attempts to manipulate the timing of extracellular ion changes during ischemia using hyperglycemia produced by intraperitoneal glucose administration have led to a delay in the onset of anoxic depolarization, and a more rapid recovery. Elevated intracellular Ca++ has been implicated in the cellular damage produced by various insults, including ischemia, in brain and other tissues. Preliminary studies with nimodipine, a selective Ca++ channel blocker, have suggested that pretreatment with this drug may delay the fall in ATP and rise in cAMP during the early minutes of ischemia in some brain regions.